Submissions for variant NM_001042492.3(NF1):c.3790G>A (p.Glu1264Lys)

dbSNP: rs863224660

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196980	SCV000254498	likely pathogenic	Neurofibromatosis, type 1	2020-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 1264 of the NF1 protein (p.Glu1264Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (Invitae, external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000492615	SCV000581279	pathogenic	Hereditary cancer-predisposing syndrome	2015-10-12	criteria provided, single submitter	clinical testing	Thep.E1264Kpathogenic mutation (also known as c.3790G>A), located in codingexon28 of theNF1gene, results from a G to A substitution at nucleotide position 3790. Theglutamicacid atcodon1264 is replaced by lysine, an amino acid with similar properties.This variant was not reported in population based cohorts in the following databases: Database of Single NucleotidePolymorphisms(dbSNP),NHLBIExomeSequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort. Additionallythis variant hasbeenseen as ade novoalteration in an individual withpersonalhistory consistent withNF1(Ambryinternal data).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious byPolyPhenand SIFTinsilicoanalyses, respectively. Based on the available evidence, p.E1264K is classified as a pathogenic mutation.
Genome-Nilou Lab	RCV000196980	SCV002559989	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003441779	SCV004170687	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Has not been previously reported as a pathogenic or benign germline variant to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25486365, 22807134, 22489043)